The increasing incidence of obesity is a recognized medical problem in developed countries. Obesity is a major factor for a number of diseases, including coronary heart diseases, hypertension, non-insulin dependent diabetes mellitus, pulmonary dysfunction, osteoarthritis and certain types of cancer. Obesity develops when the equilibrium between energy intake and energy expenditure shifts towards a positive energy balance.
Obesity can be classified as a mild (20-30% overweight), moderate (30-60% overweight) or a severe (>60% overweight) condition. Obesity is accompanied by a number of health hazards. It may impair both cardiac and pulmonary functions, perturb endocrine functions and cause emotional problems. Hypertension, impaired glucose tolerance and non-insulin dependant diabetes mellitus and hypercholesterolemia are more common conditions in overweight individuals than in individuals of normal weight. Obesity may therefore contribute to morbidity and mortality in individuals suffering from e.g. hypertension, stroke, diabetes type II, some types of cancer, gallbladder disease and ischemic heart disease. Moderate and severe cases of obesity are known to increase mortality. Colon and rectal cancer are diseases which frequently appear in obese men, and obese women often suffer from endometrial or gallbladder cancer. Furthermore, it is realized that an increase in overweight almost consequently leads to a rise in psychic and social problems.
Treatment of obesity is beneficial in that weight loss reduces the risk for mortality and morbidity. Even modest weight loss already leads to beneficial health effects. Body weight loss is known to be achieved by reducing energy intake and/or increasing energy expenditure, or promoting fat oxidation. (Clinical guidelines on the identification, evaluation and treatment of overweight and obesity in adults—The evidence report. NIH. Obes. Res. 1998; 6 (suppl): 51S-209S).
A first effective method for loosing weight is the reduction of energy intake, i.e. food intake. This is essentially possible only through a dietary treatment as malabsorption of food cannot be obtained safely either through medication or surgery. The dietary treatment must consist of a weight reducing diet as well as a maintaining diet. After a satisfactory weight loss, the energy supply must slowly be increased until the weight has stabilized on a supply of food which is nutritious and acceptable for the patient. The importance of a long-term diet is seen from the fact that only 10-20% of the patients are able to maintain their obtained reduced weight.
Secondly, increase in physical activity will lead to increased energy expenditure and consequently contribute to a negative energy balance. However, in order to obtain a significant weight loss, hours of daily physical activity are needed. Physical activity alone therefore plays a minor role in the treatment of obesity, although it is a very important supplement to other kinds of treatment. Also, physical activity can contribute to diminution of the decrease in energy expenditure which follows a dietary treatment comprising an energy restriction.
Drugs can be used in the treatment of obesity, either alone or in combination with a dietary treatment and/or increased physical activity. The drugs used in the treatment of obesity are mostly appetite reducing drugs and/or thermogenic drugs. The appetite-reducing drugs exert their effect primarily by decreasing energy intake. The reduction in food consumption is a consequence of the drug action on the brain transmitter systems that are involved in the appetite regulation. The action of these drugs is supposed to be mediated through the hypothalamus at various sites. The action can be exerted through the adrenergic, the dopaminergic or the serotonergic pathway or a combination thereof. Whichever system is involved, the final result is a stimulation of the satiety centre and eventually a simultaneous decrease in activity of the feeding centre which results in a depressed appetite. Examples of known appetite-reducing agents are e.g. ephedrine, phenylpropanolamine, amphetamines and fenfluramine.
Thermogenic drugs in the treatment of obesity are now generally accepted to possess a potential therapeutic value, and in the recent years there has been a growing interest in the search for new thermogenic compounds. The interest is primarily related to the well-accepted suggestion that obesity might be genetically determined. The genetic defect responsible for the possible development of obesity relates to a thermogenic defect (i.e. a defect in the metabolic system) of the obese person (Dulloo, A. and D. S. Miller (1989) Nutrition 5: 7-9). Although the nature of the thermogenic defect is not fully clarified, there is compelling evidence that points to a defective reactivity of the sympatoadrenal system (Astrup, A. V. (1989). Nutrition 5: 703). Dulloo & Miller (1989) Nutrition 5: 7-9) suggest that the thermogenic defect of the obese persons relates to a reduced release of norepinephrine rather than to an insensitivity to the neurotransmitter. Drugs which mimic the activity of the sympathetic nervous system and increase metabolic rate therefore offer considerable therapeutic potential for the treatment of obesity.
As used herein, the term thermogenic is meant to mean the production of heat, especially by physiological processes. A thermogenic drug is therewith a drug capable of inducing the physiologic production of heat in the human or animal body and/or fat oxidation.
Whereas a number of successful weight reduction methods are available, long term weight maintenance remains a problem. Elfhag and Rossner (Obesity Reviews (2005) 6, 67-85) reviewed a number of factors associated with successful weight maintenance after weight loss and concluded that an internal motivation to loose weight, social support, better coping strategies and ability to handle life stress, self-efficacy, autonomy, assuming responsibility in life and overall psychological strength and stability were the dominant factors that determined whether a patient would succeed to maintain his weight after an intentional weight loss. Patients are encourages to find their very unique personal solutions and inner capacities.
The reason why it is so difficult to maintain the desired weight is often contributed to the fact that in human subjects, basal metabolic rate (BMR) decreases during weight reduction, which is probably due to loss of fat free mass, fat mass and lower sympathetic nervous system activity. This effect may be particularly important in obese patients. A meta analysis of basal metabolic rate showed that formerly obese patients had a significant 3-5% lower BMR and a five-fold higher risk of having a low BMR than the never-obese (Astrup et al., (1999) Am. J. Clin. Nutr. 55:14-21).
Pharmaceutical research has addressed this problem and it was recently found that the drug Sibutramine not only provided an effect on appetite reduction but also could successfully increase energy expenditure after intentional weight loss. With a higher dose of Sibutramine, an acute thermogenic effect was observed in normal weight male subjects (Hansen et al. (1998) Am. J. Clin. Nutr. 68: 1180-1186) whereas a lower chronic dose of Sibutramine did not raise the energy expenditure but did have an effect of disinhibiting the normal reduction in energy expenditure seen with decreasing energy intake and weight loss (Hansen et al., (1999) Int. J. Obes. 23: 1016-1024).
Sibutramine is a serotonin and noradrenaline re-uptake inhibitor, and is recommended by the National Institute of Clinical Excellence (NICE) for the treatment of obesity in patients with a BMI of over 30 kg/m2 or the presence of an obesity-related disease and a BMI of over 27 kg/m2 (NICE. (2001) Guidance of the use of Sibutramine for the Treatment of Obesity in Adults. Technology Appraisal Guidance—No 31. National Institute for Clinical Excellence, London).
In a recent European trial (James et al., (2000) Lancet, 356: 2119-2125), following a 6-month run-in period on sibutramine, patients who achieved a 5% reduction in weight were randomized to either continue with sibutramine or receive placebo. At 18 months, 69% of patients on sibutramine compared with 42% of controls retained this modest 5% reduction.
However, Sibutramine may cause an increase in blood pressure and pulse (acting as a sympathomimetic) and is therefore unsuitable for hypertensive patients. In normotensive patients, treatment with sibutramine may achieve moderate weight loss for a limited period at least. Sibutramin also suffers from a number of side effects that include constipation, dry mouth, elevated blood pressure, headache, increased heart rate and sleeplessness (http://www.meridia.net/index.cfm?act=consumer_safety).
A number of other drugs have been suggested to address the problem of weight maintenance after weight loss. The drugs fenfluramine and dexfenfluramine, which acted through stimulation of 5-HT secretion as well as inhibition of 5-HT re-uptake, were withdrawn following the discovery of an association with their use and cardiac valve abnormalities (Connolly et al., (1997) New England Journal of Medicine, 337: 581-588)
Orlistat acts locally in the gut by binding to gastrointestinal lipases to inhibit fat absorption. Patients who take Orlistat with or 1 h after meals excrete approximately one-third of their ingested dietary fat in their stools, thereby reducing calorie intake. Consequently, they may have flatulence and offensive stools after a fatty meal. Trials show that Orlistat can also achieve mild weight loss of 9% at 1 years compared with 5% of placebo and may slow the regain of weight for a second year of use (Yanovski & Yanovski (2002), New England Journal of Medicine, 346: 591-602). However, Orlistat is only licensed for 2 years, and is less effective by the second year.
In conclusion, there remains a need for thermogenically active compositions that can enhance the energy expenditure of a human body in order to help maintain weight after weight loss. In particular, pharmacologically active compositions that do not suffer from the above mentioned side effects would be beneficial.